Peripheral arterial disease (PAD) is characterized by lower limb arterial obstruction due to atherosclerosis. Most of the over 8 million in the U.S. with PAD are elderly and the prevalence is increasing. Patients with PAD are undertreated with life-saving risk factor modification including raising HDL cholesterol. Presently used diagnostic methods in PAD are limited and modalities that allow study of progression and regression of disease are clearly needed. Over the past 4+ years, our multi-disciplinary team from cardiology, radiology, vascular surgery, biomedical engineering, exercise science, biostatistics and clinical trials management has developed such techniques. These include magnetic resonance (MR) measures of atherosclerotic plaque volume and characteristics in the superficial femoral artery, phosphocreatine (PCr) recovery kinetics after exercise, and first pass contrast-enhanced measures of calf muscle perfusion at peak exercise. We are presently evaluating the mechanisms of benefit of LDL reduction in PAD with these methods. In the present proposal, we aim to improve and extend the application of these novel methodologies. Aim 1 is to develop and test MR methods to quantify skeletal muscle blood flow at peak exercise in PAD without the need of a contrast agent. Twenty patients and 10 normal subjects will be studied with arterial spin labeling and blood oxygen level dependent MR and reproducibility will be determined and compared to contrast methods. Aim 2 is to compare the previously developed MR methods at 1.5T and 3T in 30 patients and 20 normal subjects. Finally, we will use the most reproducible method for perfusion and the ideal field strength as determined in Aims 1 and 2 in a clinical trial. Aim 3 is to use comprehensive MR to test the efficacy of raising HDL with a novel formulation of niacin with laropiprant that reduces flushing compared to placebo in mild to moderate PAD. Ninety patients with PAD and an ankle-brachial index between 0.4 and 0.9 will undergo comprehensive MR, exercise testing with respiratory gases, measurement of lipids and inflammatory markers at baseline and yearly for 2 years after randomization to active therapy or placebo. This study will establish the potential clinical benefit of raising HDL in PAD and will help to determine the mechanism of benefit, whether it be through macrovascular plaque regression or improved microvascular blood flow or muscle energetics. Improving the health outcomes and quality of life in patients with PAD is a major goal of this proposal.